N-acylethanolamine acid amidase (NAAA) is a cysteine amidase that plays a central role in the catabolism of saturated or monounsaturated fatty acid ethanolamides (FAEs), such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). NAAA exhibits a preference for PEA over other FAEs. PEA is a lipid produced by most of mammalian cells. PEA is involved in the regulation of inflammatory and pain processes, reduces peripheral inflammation, and exerts antinociceptive effects. Local and systemic administration of PEA alleviates pain behaviors elicited by chemical irritants, nerve damage, or inflammation. NAAA is highly expressed in inflammatory cells. NAAA inhibition offers the advantage of sustaining endogenous PEA and OEA levels under inflammatory stress conditions by blocking their degradation.
There exists an ongoing need for compounds that show proper pharmacological and pharmacokinetic profiles to be suitable for systemic administration and that are useful in treating disorders such as pain, inflammation, and neurodegenerative disorders and disease states. This invention is directed to these as well as others problems by providing, inter alia, small molecule inhibitors of NAAA as well as methods for treating pain, inflammation and neuro degenerative disorders for which there is no current and valuable pharmacological treatment.